Parkinson's disease affects 1% of adults over the age of 60 and is the second-most common neurodegenerative disease. It is characterized by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta, and clinically, it manifests with severe motor impairments including slowness of movement, bradykinesia, resting tremor, gastrointestinal disruptions, and sleep disturbances. There are currently no treatments to prevent disease onset or curtail disease progression, and identifying potential new targets for pharmaceutical interventions will be imperative to reduce disease incidence and severity. A promising target for PD therapeutics is the dopaminergic vesicle. It has been well-established by our lab and others that impaired vesicular function and capacity for dopamine-for example, as a result of under- expression of the vesicular monoamine transporter 2 (VMAT2)-can lead to progressive dopaminergic degeneration and enhanced vulnerability to dopaminergic toxicants. [Conversely, enhanced vesicular function is neuroprotective]. Our lab is therefore interested in characterizing novel targets of dopamine vesicle function, such as the synaptic vesicle glycoprotein 2C (SV2C). SV2C genotype mediates the protective power of nicotine use, which is the strongest environmental mediator of PD risk. Targeting SV2C may allow us to harness the therapeutic potential of nicotine without exposing patients to negative health consequences associated with nicotine use. We have developed SV2C-KO mice that will allow us to determine this protein's role in mediating dopamine handling and release and its functional interaction with nicotine. Preliminary electrochemistry data suggest that SV2C mediates dopamine vesicular packaging and release, providing further evidence of a potential therapeutic value for targeting SV2C in PD. The goal of this project is to demonstrate that SV2C indeed mediates dopamine handling and release, vulnerability to dopaminergic toxicity by MPTP and neuroprotection by nicotine. Results from this study will show to what extent SV2C plays a role in protecting against pathological dopaminergic degeneration, and it will evaluate its potential as a therapeutic target for PD.